Organocatalyzed synthesis of ureas from amines and ethylene carbonate

Article abstract of DOI:10.1016/j.tetlet.2010.09.107

A new solventless method for the synthesis of symmetrical and unsymmetrical ureas, starting from ethylene carbonate and amines, is reported. 1,5,7-Triazabicyclo[4.4.0]dec-5-ene(TBD) and thioureas have been found to be efficient organocatalysts for this reaction.

Full text of DOI:10.1016/j.tetlet.2010.09.107

Tetrahedron Letters 51 (2010) 6301–6304
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Tetrahedron Letters
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Organocatalyzed synthesis of ureas from amines and ethylene carbonate
⇑
Francesco Saliu , Bruno Rindone
Department of Environmental Science, University of Milano-Bicocca, Piazza della Scienza 1, 20126 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2010
Revised 20 September 2010
Accepted 22 September 2010
Available online 29 September 2010
A new solventless method for the synthesis of symmetrical and unsymmetrical ureas, starting from eth-
ylene carbonate and amines, is reported. 1,5,7-Triazabicyclo[4.4.0]dec-5-ene(TBD) and thioureas have
been found to be efficient organocatalysts for this reaction.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
2-Hydroxyethylcarbamates, 1,3-
Disubstituted ureas
Organic catalysis
Solventless reaction
1. Introduction
tion, by adding an inorganic base catalyst such as NaOMe27, CaO28
or Cs2CO3.29
Avoiding phosgene in the synthesis of isocyanates and their
derivatives, as ureas, is a hot topic in green chemistry.1,2 The syn-
thesis of ureas through phosgene substitutes is the subject of many
reviews.3 The most studied alternative routes are:
Moreover, K2CO3 and five-membered cyclic carbonates have
been recently applied in the synthesis of 2-oxazolidinones starting
from b-aminoalcohols and of 2-imidazolinones starting from
diamines.30
We report in this Letter the first attempt to replace these cata-
lysts with an organic greener catalyst.
(a) the oxidative carbonylation of amines with carbon monox-
ide (CO) under various metal catalysts,4–9
Guanidine bases and thioureas are frequently used in the dou-
ble hydrogen bonding activation of carbonyl.31,32 A further advan-
tage derives from the fact that these catalysts are commercially
available in solid supported form. Interestingly, in a recent Letter,33
the use of TBD on a solid support has been proposed in the synthe-
sis of five-membered cyclic carbonates by carboxylation of epox-
ides. The subsequent addition of amines presented here could
lead to an automated procedure to synthesize ureas.
(b) the direct reaction of carbon dioxide with amines,10–15
(c) the use of some phosgene substitutes such as carbonates,
that are less toxic and more stable.16–19
Cyclic carbonates are green reagents and solvents that are now-
adays industrially obtained from an insertion reaction of carbon
dioxide into epoxides, using cheap catalysts such as homogeneous
quaternary ammonium salts.20 This is one of the most important
methods for CO2 fixation21 and efforts are in progress all over the
world to find more efficient heterogeneous catalysts.22,23
2. Results and discussion
The reactivity of cyclic carbonates with nucleophiles can be ex-
plained on the HSAB principle basis.24 Hard bases such as amines
open the ring of cyclic carbonate reacting at the trigonal carbon
of the carbonyl group to give 2-hydroxyethylcarbamates.
By using specific cyclic carbonates, which can form activated car-
bamates, isocyanates and ureas can be subsequently obtained.25,26
As a more general procedure, symmetrical and unsymmetrical
ureas are formed from 2-hydroxyethylcarbamates via transamina-
The first set of experiments was intended to optimize the reac-
tion conditions for the synthesis of symmetrical 1,3-disubstituted
ureas. Various organic catalysts and solvents (Table 1) were tested
in the synthesis of 1,3-dicyclohexylurea (2a) from ethylene car-
bonate and cyclohexylamine (1a) (Scheme 1). TBD (1,5,7-triazabi-
cyclo[4.4.0]dec-5-ene) and 1,3-diisopropylthiourea were most
effective in giving 1,3-dicyclohexylurea in good yield under sol-
ventless conditions (Table 1, entries 6 and 12). The lower conver-
sion obtained in solution are presumably related with the lower
reaction temperature.
We tested also if 1,3-dicyclohexylurea had an autocatalytic
effect on the reaction (entry 16) by acting as hydrogen bond donor
⇑
Corresponding author. Tel.: +39 02 64482813; fax: +39 02 64482839.
E-mail address: francesco.saliu@unimib.it (F. Saliu).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.107

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F. Saliu, B. Rindone / Tetrahedron Letters 51 (2010) 6301–6304
Table 1
Effect of the catalyst and the solvent in the synthesis of 1,3-dicyclohexylurea from ethylene carbonate and cyclohexylamine
N
N
S
N
N
S
O
Catalysts:
N
H
N
H
N
H
N
N
H
N
H
N
H
N
H
N
DMAN
1,3-dicyclohexylurea
TBD
1,3-diphenlythiourea
1,3-diisopropylthiourea
DBU
Entry
Catalyst
Solvent
Temperature (°C)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
13
14
15
16
17
DBU
DBU
CH2Cl2
None
THF
CH2Cl2
CH2Cl2
None
CH2Cl2
None
Ethyl acetate
Toluene
None
None
CH2Cl2
None
40
120
65
40
40
44
62
15
21
63
76
56
72
10
5
51
88
65
42
62
4
p-Toluenesulfonic acid
p-Toluenesulfonic acid
1,3-Diisopropylthiourea
1,3-Diisopropylthiourea
1,3-Diphenylthiourea
1,3-Diphenylthiourea
1,3-Diphenylthiourea
1,3-Diphenylthiourea
DMAN
120
40
120
75
110
120
120
100
120
80
120
120
40
TBD
TBDb
TBDc
TBD
None
Acetonitrile
None
None
1,3-Dicyclohexylurea
1,3-Dicyclohexylurea
6
7
CH2Cl2
a
Isolated yields in 1,3-dicyclohexylurea. Reaction conditions: 20 mmol of cyclohexylamine, 10 mmol of ethylene carbonate, 0.2 mmol of
catalyst, reaction time 180 min.
b
In autoclave.
0.02 mmol of catalyst.
c
NH2
H
N
H
N
O
solvent
catalyst
OH
OH
O
+
2
O
+
O
2a
1a
Scheme 1. Preparation of 1,3-dicyclohexylurea from cyclohexylamine and ethylene carbonate.
like thioureas, but we observed no conversion, probably due to the
poor solubility of this compound in organic solvents and in the sol-
ventless mixture too.
H
N
O
R1
OH
The generality of the reaction was examined by using various
amines, as shown in Table 2. Aliphatic primary amines gave from
good to excellent yields in the corresponding symmetrically
disubstituted ureas, no conversion was observed with aromatic
amines. Aliphatic secondary amines gave only the corresponding
2-hydroxyethylcarbamates.
The fact that secondary amines do not give ureas and the obser-
vation of traces of isocyanates in the crude reaction mixture from
primary amines both suggest that isocyanates could be intermedi-
ates in these reactions. In an attempt to isolate cyclohexylisocya-
nate the best result was achieved by carrying out the reaction in
dichloromethane with paratoluenesulphonic acid, obtaining this
N
O
R1
OH
base catalyst
R1
OH
3
O
O
OH
N
O
N C O
R1
+
4
O
O
H
N
H
N
+
H2N
R1
R1
N C O
R1
1
R1
4
O
2
Scheme 2. Supposed hydrolysis mechanism of 2-hydroxyethylcarbamates.
NH2
H
N
H
N
H
N
OH
OH
O
R1
OH
+
+
O
O
TBD
2a
3a
1a
Scheme 3. Reverse reaction to confirm the reversibility. KE = [2a][HO(CH2)2OH]/[3a][1a].

F. Saliu, B. Rindone / Tetrahedron Letters 51 (2010) 6301–6304
6303
It has been reported34 that, in the presence of basic amines, car-
bamates dissociate into isocyanates and alcohols, and afterward
isocyanates react with amines to form ureas. All these were shown
to be equilibrium reactions. Similarly, in the reaction reported
herein, the in situ generated 2-hydroxyethylcarbamate (3) could
undergo a base catalyzed hydrolysis, that involves an elimination
step (Scheme 2). This hypothesis is slightly different from the
transamination reported with inorganic catalysts.28 To confirm
the reversibility and to determine the equilibrium constant we
put 1,3-dicyclohexylurea and an excess of ethylene glycol (100:1)
in dichloromethane at 50 °C for 48 h and we checked the formation
of the corresponding 2-hydroxyethylcarbamate (3a) (Scheme 3).
We found a very high value of the K of the equilibria (ca
3.8 Â 104) that is probably related with the poor solubility of 1,3-
dicyclohexylurea. Thus, the precipitation of products is the key that
can enable our solventless reaction to go to completion. Investiga-
tions are underway to have further details of the mechanism.
On the basis of these observations we developed a two-step
procedure for the synthesis of unsymmetrical ureas (Scheme 4).
In the first step a primary amine (1) reacts with ethylene carbonate
to give the corresponding 2-hydroxyethylcarbamate (3). In the sec-
ond step the 2-hydroxyethylcarbamate reacts under organic base
catalysis with another primary amine or with a secondary amine
to give disubstituted (5) or trisubstituted ureas (6), respectively
(Table 3). Starting from secondary amines, in any case, no ureas
are formed. Although this method is fast and high yielding, the for-
mation of symmetrical ureas as side products is its major drawback
and column chromatography and recrystallization are needed to
obtain the desired products in high purity.
Table 2
TBD catalyzed synthesis of 1,3-symmetrically disubstituted ureas
Entry
1b
Amine
Product
Yielda (%)
84
O
O
NH2
N
H
N
H
NH2
2b
3b
86
74
N
H
N
H
H
N
H
N
NH2
O
H
N
H
N
NH2
4b
5
68
76
O
H
N
H
N
NH2
O
O
NH2
6
7
88
—
N
H
N
H
H3CO
NH
NH2
No reaction
O
8b
9
80
96
N
O
OH
OH
N
O
NH
O
O
O
OH
N
O
10
11
12
13
94
—
NH
O
In conclusion, the synthesis of 1,3-disubstituted symmetrical
and unsymmetrical ureas from ethylene carbonate and the corre-
sponding amines was performed in good to excellent yields using
TBD as catalyst under solventless conditions.
No reaction
No reaction
No reaction
NH
NH
NH
3. Experimental
—
All chemicals were purchased from Sigma–Aldrich and used
without further purification. Reaction products were characterized
by comparison with the IR, GC–MS, and 1H NMR of known com-
pounds. Yields were determined after isolation.
—
a
Yields refer to isolated pure products characterized by IR, GC–MS, and 1H NMR.
3.1. Representative experimental procedure for the synthesis of
1,3-disubstituted symmetrical ureas (2)
Reaction conditions: 20 mmol of amine, 10 mmol of ethylene carbonate, 0.2 mmol
of TBD, 120 °C, 120 min.
b
90 °C.
Experiments were carried out by mixing ethylene carbonate
(10 mmol) with a primary amine (1, 20 mmol) and the catalyst
(0.2 mmol) and by heating at the desired temperature for
120 min. The reaction mixture was cooled and the crude product
was purified on silica gel (R = 100) by eluting with the mixture
dichloromethane–ethyl acetate (85:15). The procedure for the iso-
product in 13% yield. Reaction monitoring by IR spectroscopy
shows the OH band after few seconds from the start and subse-
quently the formation of the characteristic band of isocyanate
and of the bands of 1,3-dicyclohexylurea.
H
N
H
N
H
N
H
N
H
N
H
N
R1
R2
+
R2
R2
R1
+
R1
NH2
R2
O
2
O
O
5
O
O
5a: R1=cyclohexyl, R2=benzyl
5b; R1=pentyl, R2=allyl
TBD
R3
HN
OH
H
N
O
O
R1
N
R1
OH
+
NH2
C
R4
O
O
HO
1
R3
H
N
H
N
H
N
4
3
TBD
N
R1
R1
R4
R1
+
O
O
6
2
6a: R1=cyclohexyl, R3=R4=ethyl
Scheme 4. TBD-catalyzed synthesis of unsymmetrical ureas.

6304
F. Saliu, B. Rindone / Tetrahedron Letters 51 (2010) 6301–6304
Table 3
Yield in the TBD-catalyzed synthesis of unsymmetrical ureas
Entry
First amine added
Second amine added
Unsymmetrical urea product
Yielda (%)
1
2
3
4
5
Cyclohexylamine
Pentylamine
Cyclohexylamine
Cyclohexylamine
Piperidine
Allylamine
Morpholine
Hexylamine
Benzylamine
Allylamine
Diethylamine
Piperidine
Cyclohexylamine
Morpholine
Pentylamine
Morpholine
(5a)
(5b)
(6a)
(6b)
None
(6c)
60
58
88
92
—
90
—
65
6
7b
8b
None
(6d)
a
Yields refer to isolated pure products characterized by IR, GC–MS, and 1H NMR. Reaction conditions: 20 mmol of ethylene carbonate,
20 mmol of the first amine, 20 mmol of the second amine, 0.2 mmol of TBD catalyst, 90 °C, 180 min.
b
0.2 mmol of 1,3-diisopropylthiourea catalyst.
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a primary amine (1,
10 mmol) were heated at 70 °C for 1 h to afford the corresponding
2-hydroxyethylcarbamate (3). This transformation can be sped up
by reacting the solventless mixture under microwave irradiation.
TBD (0.2 mmol) and a second amine (another primary amine to af-
ford a disubstituted urea (5) or a secondary amine to afford a tri-
substituted urea (6), 10 mmol) were added to the reaction
mixture and were heated at the desired temperature for 120 min.
N-Allyl-4-morpholinecarboxamide 6c IR (KBr): 3268, 2911, 2804,
1742, 1530 cmÀ1; 1H NMR (400 MHz, CDCl3) d: 3.22–3.71 (m, 10H),
5.05 (d, J = 9.2 Hz, 1H), 5.13 (d, J = 16.1 Hz, 1H), 5.62 (br, 1H) 5.76
(m, 1H); 13C NMR (100 MHz, CDCl3) d 43.5, 57.2, 76.7, 116.1,
134.9, 157.1; MS (EI 70 eV) m/z: 170 (M+), 141, 127, 114, 86, 70, 57.
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Acknowledgments
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We warmly thank Giovanni Di Gennaro, Matteo Berra, Emanu-
ele Fossati, Marcello Dusini, Alessandra Saliu, and Moira Pringle for
their collaboration.
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